It is well known in the aminoacids and peptides chemistry that it is essential to regioselectively protect the terminal amino group (in ω) of the side chain of lysine and its analogues. This allows reacting selectively the α amino group and, in case, orthogonally protecting the α and ω amino groups. The possibility of selectively introducing two protecting orthogonal groups into an α,ω-diaminoacid increases its potential uses in general chemistry and particularly in pharmaceutical chemistry. The alkoxycarbonyl groups (or carbamates) are the most versatiles and widely used protecting groups for aminoacids.
Because of the synthetic importance of the protection of α,ω-diaminoacids in the ω position, several studies have been dedicated to this subject. The classical method, still widely applied, involves the formation of a copper II complex to block the α nitrogen and to selectively protect the ω position (J. Biol. Chem. (1941), 140, 705-10). This methodology is long and tedious since it requires several reactions: first the formation of the copper complex, then the α protection and eventually the liberation of the complex with EDTA or hydrogen sulfide. Due to its toxicity, residuals of copper must not pollute the protected aminoacid and this requires a further purification procedure (Tetrahedron Lett. (2004), 45(50), 9297-9298). Moreover the maximum concentration of copper in wastewaters is set by the Italian law at 0.1 ppm; in addition to the cost of the metal itself, also the cost of disposal and decontamination of the mother liquors must thus be taken into account. In conclusion this methodology is suitable for small preparations on a laboratory scale, but not for industrial productions.
Chemists have tried over time several alternatives, among them the use of special reagents such as, in the case of an introduction of a BOC group in the e position of a lysine, Boc-hydroxyquinoline (Liebigs Ann. Chem. (1968), 716, 216-18) and 2-(Boc-oxyimino)-2-phenylacetonitrile (Org. Prep. Proced. Int. (1983), 15(6), 379-85). However all these reagents either give low yields or are expensive, making them unsuitable for large scale application.
Finally some benzotriazole carbamates, such as Boc-benzotriazole (U.S. Pat. No. 4,942,248; Synth. Commun. (1997), 27(9), 1623-1630) and Z-benzotriazole (Synthesis (1986), (11), 958-60) have been used to protect aminoacids, but never for α,ω-diaminoacids, nor any regioselectivity of their reactions has been reported.
From the drawbacks of the known processes it is clear that there is still the need for a process for the preparation of ω-alkoxycarbonylamino-α-aminoacids and of α,ω orthogonally diprotected diaminoacids from α,ω-diaminoacids which is applicable on an industrial scale with high yields and uses cheap and non-polluting reagents.